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While they characteristically present with metabolic and neurological crises, growing evidence reveals a significant burden of chronic immune dysregulation in some disorders and patients. This review provides a synthesis of clinical and mechanistic evidence discussing immune dysregulation in OAs. Cytopenia can occur in OAs and predispose patients to recurrent and severe infections. Adaptive immune deficits, such as hypogammaglobulinemia, reduced B and T cell populations, and impaired vaccine\u2010specific antibody responses, including to diphtheria and tetanus in MSUD and to the inactivated COVID\u201019 vaccine in propionic acidemia, have also been reported. Additionally, some case series note hyperinflammatory conditions, such as hemophagocytic lymphohistiocytosis. Mechanistic studies indicate that accumulated metabolites disrupt innate and adaptive hematopoietic progenitor function, mitochondrial homeostasis, and inflammatory signaling. Emerging therapeutic avenues, such as gene and mRNA\u2010based therapies, hold the potential to improve or normalize the biochemical phenotype in OAs. While their impact on immune abnormalities remains largely unexplored, future clinical trials offer an opportunity to systematically assess potential effects on immune parameters. OAs are increasingly recognized as disorders with intrinsic immune dysregulation, extending beyond their well\u2010characterized metabolic and neurological manifestations. Future clinical trials will benefit from including immunological endpoints to evaluate immunological recovery for novel therapies.<\/jats:p>","DOI":"10.1002\/jimd.70203","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T06:51:05Z","timestamp":1782888665000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune Dysregulation in Branched Chain Organic Acidemias"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1404-114X","authenticated-orcid":false,"given":"Abdul L.","family":"Shakerdi","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"School of Medicine, Trinity College Dublin  Dublin 2 Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Drda","sequence":"additional","affiliation":[{"name":"Department of 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